The overall goal of the proposed research is to investigate a fundamental problem in neuroscience--the physiological basis of learning and memory. The proposed studies will focus on the elucidation of the mechanisms underlying sensitization, a simple form of nonassociative learning, the memory for which has both short- (minutes) and long- (days) term forms. The first aim is to investigate biophysical correlates of long-term sensitization and the interactions between long- term sensitization and the processes that underlie the synaptic profile. Particular attention will be paid to the "synaptic profile," which is defined as the monosynaptic PSPs produced in a motor neuron by a brief burst of activity in a presynaptic sensory neuron. Such a burst of activity mimics the response of the system to behaviorally relevant stimuli. Moreover, the synaptic profile simultaneously engages several processes that regulate synaptic transmission and plasticity. Thus, investigating the synaptic profile has provided new insights to the mechanisms of synaptic plasticity. These insights were not revealed previously by studies that used the more traditional approach of investigating synaptic responses to a single presynaptic spike. The specific objectives of the first aim are: 1) Characterize additional correlates of long-term sensitization, such as changes in the synaptic profile and presynaptic spike waveform and cellular changes following one vs. four days of training; 2) Investigate the role of the growth factor TGF-[3 in the expression of long-term sensitization; and 3) Examine the contribution of persistently active kinases to the expression of long-term sensitization. The second aim is to investigate the role of the synaptic vesicle protein synapsin and its phosphorylation in short- and long-term synaptic plasticity at sensorimotor synapses. The specific objectives of the second aim are: 1) Examine the functional role of synapsin and its phosphorylation in short-term homo- and hetero-synaptic plasticity; 2) Investigate the regulation of the subcellular localization of synapsin by 5-HT; and 3) Investigate the role of synapsin in long-term plasticity. The third aim is designed to examine possible contribution of postsynaptic processes to the synaptic profile and its modulation. The specific objectives of the third aim are: 1) Investigate the contribution of receptor desensitization to the synaptic profile; 2) Determine the ways in which heterosynaptic modulation modifies the processes that underlie the synaptic profile; and 3) Determine the role of desensitization in the synaptic facilitation underlying long-term sensitization. PERFORMANCESITE(S) (organizationc, ity,state) The University of Texas Health Science Center at Houston Houston, Texas KEY PERSONNEL.See instructionsU. secontinuatiopnagesas neededto providethe requiredinformationin theformat shownbelow. StartwithPrincipaIlnvestigatoLr.istallotherkey personnelinalphabeticaolrder,lastnamefirst. Name Organization Roleon Project John H. Byrne University of Texas Health Science Center Principal Investigator Gregg Phares University of Texas Health Science Center Research Fellow Randall Hayes University of Texas Health Science Center Research Fellow Diasinou Fioravante University of Texas Health Science Center Graduate Student Evangelos Antzoulatos University of Texas Health Science Center Graduate Student Andrew Bean University of Texas Health Science Center Consultant Leonard J. Cleary University of Texas Health Science Center Consultant Arnold Eskin University of Houston Consultant DisclosurePermissionStatement.Applicableto SBIR/STTROnly. Seeinstructions. [] Yes [] No DPHS398(Rev.05/01) Page2 FormPage2 a [] Principal Investigator/Program Director (Last, first, middle): Byrne, John H. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbem Face Page .................................................................................................................................................. 1 Description,